Sunday, August 1, 2010

Depression crashed your party

I've told you before I like Dr. Maes. Turns out he's been working the depression = inflammation angle for the past twenty years, isolating all the cellular mechanisms while we were all busy getting bored by drug reps peddling their newest serotonin reuptake inhibitors.

Maes is not only brilliant, but cranky. The main page of his website is devoted to accusing a Dr. Dantzer of stealing his ideas, and much of the introduction of this brand new paper harps on the fact that Dowlati's recent major meta-analysis of depression and inflammation left out much of Maes' work. Fortunately Maes' current paper cites 39 of his previous papers - so nothing will be left out here. I've got your back, cranky Belgian depression and inflammation researcher!

I'll begin by describing the immune system. It's complicated. Imagine an A-list party with all sorts of different security checks and bouncers. There are guys on the perimeter keeping the unwashed masses out, then there are guards on the inside keeping an eye on the elite, and maybe even spies working the crowd, searching for any crashers. The different security forces of our immune system have different names and duties, too. There are the B cells which work via little protein tags called antibodies (known as the "humoral immune system.") Then there are the natural killer cells, hungry macrophages, and other elite shock troops. Finally, you have the cell-mediated immunity, primarily the T cells, who run around messing with anyone who looks like he doesn't belong.

In several of the last blog posts, I mentioned high levels of IL-6 and TNFalpha as markers of depression. These inflammatory cytokines (among many more, such as IL-2, IL-12, interferon gamma, and biomarker neopterin) activate and prime the T cells, who then go out and do their killing. Therefore inflammation means, in a nutshell, that the body's security forces are out there, and the cell-mediated part of our inflammatory reaction is the major cause of the symptoms of depression.

Out-of-whack cell-mediated immunity has also been implicated in lupus, diabetes mellitus, schizophrenia, rheumatoid arthritis, several cancers, multiple sclerosis, and Grave's disease. But Maes has been able to link various participants in cell mediated immunity to many of the major symptoms of depression, including the "vegetative" symptoms (poor sleep, poor eating), the somatic symptoms (increased worry about illness and increased aches and pains), and the decreases of neurotransmitters serotonin and norepinephrine. He links it to the alterations in the HPA axis. Not to mention the actual inflammation in the hippocampus itself. To put it simply, Maes has described the complex biochemical mechanisms of depression using a single overriding, reasonable, and realistic theory of cell-mediated immunity. This is like learning the beautiful ins and outs of how too much fructose causes metabolic syndrome. In a word, awesome.

Maes and other researchers start by measuring a T-cell activating cytokine called sIL-2R. This little bugger is higher in the blood and CNS of people with cerebral lupus, depression, and mania. The worse the symptoms, the higher the levels, and the levels fall when the depression, lupus, and mania symptoms go into remission. Pretty telling. Other markers of cell-mediated immunity (soluble CD8 antigen and other T-cell surface markers, and levels of interferon gamma) follow a similar pattern.

One interesting tidbit - a lot of inflammatory disorders respond to steroids, which suppress the immune response. Asthma, multiple sclerosis, inflammatory bowel. Depression will often get worse with steroids, and Maes figures that's because depression is driven primarily by the T-cells, which are steroid-resistant compared to other parts of the immune response. In case you were wondering.

But let's get back to the actual mechanisms. I reviewed one in a previous post (a useful diagram is linked here). Inflammation causes our body to preferentially make tryptophan, the precursor to serotonin, into kynurenic and xanthurenic acid. Not only does this mean we have less happy, relaxing serotonin around, but kynuretic has the tendency to make us anxious and depressed all on its own. More specifically, T helper cells and indoleamine 2,3-dioxegenase (IDO), parts of our cell-mediated immune response, lower our serotonin levels and make us depressed. This mechanism is true of bipolar depression, major depression, adolescent depression, depression in heart failure patients... you name it, and IDO is smacking down our serotonin. Interferon alpha treatment for hepatitis C or multiple sclerosis will activate the very same mechanism to make us depressed. In animal models, specific cell-mediated immune activation causes lack of interest and changes and sleep and appetite consistent with the similar human symptoms of depression.

Antidepressants work by suppressing the cell-mediated immune response in specific ways. All major classes of antidepressants have been shown to have this effect in various models - tricyclics, SSRIs, SNRIs - they block the production of IL-6 and TNF alpha in immune cells, and also block a number of other acute inflammatory phase proteins, such as C-reactive protein and haptoglobin. Antidepressants are anti-inflammatory, and never-treated depressed individuals will have much higher markers of inflammation than those who are treated. While there are several studies of neuroimaging showing similar changes in metabolism of the brain with response to antidepressants or psychotherapy, I found only one that specifically measured psychotherapy and inflammation, from 2009 in depressed cancer patients. I was also able to find this study of yoga reducing C-reactive protein, IL-6 and other markers of inflammation. I think it makes sense to assume that any successful treatment of depression will be anti-inflammatory. Dance Dance Revolution did not reduce inflammatory markers in obese kids, however. Who knew?

Mood stabilizers, such a lithium and depakote, also affect the ratios of key inflammatory cytokines. Like the antidepressants, they suppress the cell-mediated immune response in specific ways that affect neurotoxicity and neuroplasticity.

I wish we had more evidence-based lifestyle and dietary trials for psychiatric disorders. Not just (probably biased) studies of medications and a few of psychotherapy, and not just a bunch of epidemiological studies. What if we knew for certain that dietary changes could could stop the inflammation in the first place? If I'm right about my paleolithic-style approach, then I could actually prescribe grass-fed steak (not currently FDA-approved) in addition to fish oil. Well, I'll keep looking!

I too just discovered this blog and it's great! I have spent the past hour or so scanning through several posts in regards to anxiety. Anxiety is one of those elusive things that everyone seems to have in varying forms, but no one has found the cure. I generally avoid the doctor if possible, but broke down a few weeks ago after several bouts of anxiety induced dizziness. And guess what the doc prescribed? Beta blockers. I laughed, literally at her, but walked away with the prescription anyway. I decided to humour her and try one out next time I was driving which is generally what causes my anxiety) and had a severe bout of dizziness. And what do you know--it seemed to exacerbate the symptoms. I have implemented the paleo style diet plan and feel generally better, but still have issues in certain situations. I am wondering if you know of any specific foods or supplements that are thought to heal or prevent symptoms of anxiety? Thanks and keep up the great work!Lindsay

Hi Lindsay. Anxiety is tough, and in my opinion needs a full bore approach - lifestyle modification and therapy are exceedingly important. My favorite book for anxiety is "The Anxiety and Phobia Workbook" by Bourne. Breathing into a paper bag or sipping ice water can also be helpful for acute attacks in the car, once you've pulled over to the side of the road!. So far as supplements - for anyone with mental illness I would recommend recording a week or two on fitday to see if there are any glaring vitamin and mineral issues, then repleting what needs to be repleted. Have the vitamin D levels checked, and aim for a goal level of 50 or higher.

So far as other supplements, a recent study came out about chamomile that looked very promising: http://www.medconnect.com.au/tabid/84/ct1/c336280/Default.aspx. Randomized controlled trial, even! Patients took 220mg capsules of chamomile (up to 5 capsules, depending on response), and it was helpful. Not sure where you can get your hands on pharmaceutical grade chamomile.

Of course, I must recommend that you proceed with the blessings of your doctor...

Emily,sIL-2r is a pretty cool molecule. and, there is a humanized antibody against it called daclizumab. Daclizumab is mainly used for immune suppression in renal transplant, but back in the day i was involved in a trial using it in leukemia and lymphoma. it's a pretty cool antibody that will sop up just about all the sil-2r in the body as well as take out the t cells with upregulated expression of it (CD25). it's one of the few cell surface ligands that is cleaved and present in the blood. i have a paper 1. Hagg DS, Junghans RP. Measurement and biological correlates of antibody bioactivity during antibody immunotherapies. Journal of Immunological Methods. 219(1-2):7-21;1998 Oct 1that describes the kinetics of antibody binding with soluble receptor.if upregulation of t reg cells expressing cd-25 is a culprit in depression, this would be a pretty straightforward study to do.

of course that isn't really in keeping with the dietary changes to improve life that you and i have discussed, but it is at least testable.plus, the antibody has few side effects and can be dosed once per month.

Wow, Dan. I'm going to have to follow up on that one. I'll make some inquiries around the medical school as I'll be back there teaching in the fall. Maes had quite a few references for the soluble IL2 part of his paper - I'll chase some of those down and see what the methods were. Maybe the study has already been done or is in the process of being done, seeing as how it is the logical next step. You did that paper in medical school? Cool.

Hi Emily, what do you say, then, to an individual who has a family history of inflammatory diseases and wants to take an anti-depressant as a preventive measure, as a way to minimize the likelihood of developing an inflammatory disease? This in addition to diet, exercise, yoga, etc. If anti-depressants are anti-inflammatory, why not take them as one takes fish oil supplements? Best, Kevin P.S. This really will be my last question on this head.... Cheers.

Hi Kevin - I would say follow the data! Antidepressants have been studied in those with depression or anxiety. Why add an antidepressant if one is not depressed and following an anti-inflammatory diet whatever the pedigree, without data?

Just one interesting study (can't find the reference now, but I saw it presented at a conference) where teenagers with high risk of developing schizophrenia (1st degree relatives with the illness and already exhibiting signs of social withdrawal, paranoia, but no frank psychotic symptoms) were randomized to therapy+antipsychotics or therapy+antidepressants. If I'm remembering correctly, only one of the kids in the antidperessant group developed schizophrenia over the next 3 or 4 years, whereas maybe 20-30% of the antipsychotic group developed schizophrenia, which is about what you would expect for no treatment at all. It was a small study, maybe 40 people, but I think more evidence that antidepressants can be neuroprotective. No idea about their diets, obviously.

One last thing - antidepressants are a pain! They can have some major side effects. No one should use them unless the benefits convincingly outweigh the risks. I'm definitely not in the "SSRIs in the water" camp. There are better ways to reduce systemic inflammation than statins and SSRIs.

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About Me

Emily Deans, M.D.: I'm a psychiatrist in Massachusetts searching for evolutionary solutions to the general and mental health problems of the 21st century. Disclaimer: This information is for educational purposes only, and is in no way intended to be personal medical advice. Please ask your physician about any health guidelines seen in this blog, as everyone is different in his or her medical needs.